Stochastic Optical Reconstruction Microscopy Imaging of Multiple System Atrophy Inclusions Suggests Stepwise
Benoît Vovard1,2, Alexia Bodin1,2, Julien Gouju2,3
1Univ Angers, Equipe MitoLab, Unité MitoVasc, Inserm U1083, CNRS 6015, SFR ICAT, Angers, France.
Background:
The architecture and composition of glial (GCI) and neuronal (NCI) α-synuclein inclusions observed in multiple system atrophy (MSA) remain to be precisely defined to better understand the disease.
Methods:
Here, we used stochastic optical reconstruction microscopy (STORM) to characterize the nanoscale organization of glial (GCI) and neuronal (NCI) α-synuclein inclusions in cryopreserved brain sections from MSA patients.
Results:
STORM revealed a dense cross-linked internal structure of α-synuclein in all GCI and NCI. The internal architecture of hyperphosphorylated α-synuclein (p-αSyn) inclusions was similar in glial and neuronal cells, suggesting a common aggregation mechanism. A similar sequence of p-αSyn stepwise intracellular aggregation was defined in oligodendrocytes and neurons, starting from the perinuclear area and growing inside the cells. Consistent with this hypothesis, we found a higher mitochondrial density in GCI and NCI compared to oligodendrocytes and neurons from unaffected donors (P < 0.01), suggesting an active recruitment of the organelles during the aggregation process.
Conclusions:
These first STORM images of GCI and NCI suggest stepwise α-synuclein aggregation in MSA. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Insights
This study used STORM microscopy to investigate α-synuclein inclusions in multiple system atrophy (MSA). Findings reveal a stepwise aggregation process in both glial (GCI) and neuronal (NCI) cells, suggesting a common mechanism.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Multiple system atrophy (MSA) is characterized by glial (GCI) and neuronal (NCI) α-synuclein inclusions.
- The precise architecture and composition of these inclusions are not well understood.
- Understanding these inclusions is crucial for deciphering MSA pathogenesis.
Purpose of the Study:
- To characterize the nanoscale organization of α-synuclein inclusions in MSA.
- To investigate the potential common aggregation mechanisms in glial and neuronal cells.
Main Methods:
- Stochastic optical reconstruction microscopy (STORM) was employed.
- Cryopreserved brain sections from MSA patients were analyzed.
- Nanoscale organization of GCI and NCI was examined.
Main Results:
- STORM imaging revealed a dense, cross-linked internal structure of α-synuclein in all GCI and NCI.
- The architecture of hyperphosphorylated α-synuclein (p-αSyn) inclusions was similar in glial and neuronal cells.
- A common stepwise intracellular aggregation sequence, starting from the perinuclear area, was observed in both cell types.
- Higher mitochondrial density was noted in GCI and NCI compared to unaffected cells, suggesting organelle recruitment.
Conclusions:
- These findings provide the first STORM images of GCI and NCI in MSA.
- The results suggest a stepwise α-synuclein aggregation process common to both glial and neuronal cells in MSA.
- This sheds light on the aggregation mechanisms underlying MSA pathology.
